1. Field of the Invention
This invention relates to novel compounds that are sigma binding site agents.
2. Background Information
Use of drugs with well-demonstrated effectiveness in treatment of psychiatric disorders has become widespread over the last thirty years. Presently about twenty percent of the prescriptions written in the United States are for medications intended to change mood, thinking, or behavior. Neuroleptic agents such as chlorpromazine and haloperidol are the primary medications used to treat schizophrenia and other psychoses. Most of the numerous clinically effective antipsychotic drugs currently available are dopamine (D.sub.2) receptor antagonists and produce essentially the same spectrum of adverse effects. Examples of adverse effects include extrapyramidal side effects such as various dystonias which may resemble Parkinson's disease. Tardive Dyskinesia, characterized by involuntary movements consisting of sucking and smacking of the lips, lateral jaw movements, and fly-catching dartings of the tongue, is a serious and potentially irreversible adverse effect which occurs in up to twenty percent of patients treated with currently available antipsychotic agents.
The recently identified central nervous system sigma binding sites are potential targets for development of antipsychotic drugs that lack the adverse effects associated with available D.sub.2 antagonists. Sigma binding sites were initially postulated by Martin et al., J. Pharmacol. Exp. Ther., 197: 517-532, 1976, to explain the psychotomimetic effects of(+)-benzomorphans such as N-allynormetazocine (SK&F 10047). It was subsequently demonstrated that sigma sites could be selectively labeled by the ligands [.sup.3 H]ditolylguanidine (DTG) and [.sup.3 H] (+)-3-(hydroxyphenyl)-N-(1-propyl)piperidine [(+)-3-PPP]. Both psychotomimetic agents, such as the (+)benzomorphans and PCP, and certain antipsychotic drugs, including haloperidol, displace [.sup.3 H]DTG and [.sup.3 H](+)-3-PPP from sigma sites. Because haloperidol reverses the stimulant and psychotomimetic effects of SK&F 10047 and PCP, it has been argued that haloperidol may be a sigma "antagonist" and that the sigma "antagonist" activity of this and related agents may contribute to their antipsychotic effects. Thus, a selective sigma "antagonist" that, unlike haloperidol, is relatively inactive at dopamine receptors could evidence antipsychotic activity without producing extrapyramidal side effects or tardive dyskinesias associated with currently available dopamine antagonist neuroleptics.
Rimcazole is the first sigma-selective antipsychotic for which results of a substantial number of clinical trials have been reported. Although rimcazole has shown some effectiveness in treating schizophrenia, it is only moderately potent at sigma sites and has been shown to induce seizures. Chouniard, G. and L. Annable, Psychopharmacol. 84: 282-284 (1984); Guy, W. et al., Drug Dev. Res. 3: 245-252 (1983). Remoxipride, another sigma site binding agent which has been tested in humans, also has significant D.sub.2 blocking potency. Thus, there remains a need for sigma-selective agents which effectively treat psychoses without producing adverse effects.
It has now been found that certain derivatives of chromone (4H-1-benzopyran-4-one) compounds (Formula I, below) are potent and selective for sigma binding sites and, like haloperidol, antagonize the stimulant/psychotomimetic effects of the dopamine agonist, amphetamine, and presumed sigma agonists such as PCP. For this reason, the novel chromones, like haloperidol, will be referred to as sigma antagonists. Note that the designation of these agents as sigma antagonists refers to the in vivo pharmacological profile of the compounds, not to the mechanism of action at sigma receptors/binding sites. Also, "receptor" as used herein refers to true, membrane-bound receptors and to other binding sites.
Jesthi, P. K. et al. describe .beta.-diethylaminoacetoxy, .beta.-aminoethoxy, and .beta.-diethylaminoethoxy flayone derivatives found to possess antispasmodic and antihistaminic properties. J. Indian Chem. Soc. 42: 105-108 (1965).
German Patent No. 1,054,091 (1959) discloses a series of N-substituted-2-phenyl-7-aminoalkoxy chromone compounds reported to have vasodilator activity.
U.S. Pat. No. 3,810,896 (1974) discloses various 4-[.omega.-(flavone-7-yloxy)]-alkyl piperazine compounds reported to have antiinflammatory and antiedematous action.
U.S. Pat. No. 4,678,787 (1987) discloses 4H-1-benzopyran-4-ones and their sulfur analogues for treatment of psychosis including schizophrenia.